The goal of this project is to develop a drug treatment which limits the extent of nervous system damage caused by a stroke or brain/spinal cord trauma. The drug treatment we seek might also be useful in treating any neurological disorder (such as epilepsy) or neurodegenerative disease (such as Huntington's or Alzheimer's disease) where there is reason to believe that the disorder/disease involves, or is caused by, excessive excitation of nerve cells by agonists of the NMDA sub-type of glutamate receptor. The starting point for this project was our finding that certain substituted guanidines were use-dependent blockers of the cation channel associated with the NMDA receptor. These guanidines were found to protect nerve cells both in vitro and in vivo from glutamate-induced cell death. In Phase I of the project we synthesized a number of new substituted guanidines with substantially improved affinity and dramatically enhanced selectivity for the PCP receptor. They show excellent neuroprotective properties in vitro and in vivo. The general aim of Phase II of this project is to pursue the development of the most promising compound as a neuroprotective drug while continuing to expand the compound series to increase our understanding of the structure- activity relationships and to gain further candidates for drug development.